The mechanism by which dietary PO4 deprivation increases 1,25-(OH) 2-D levels in not known. Although previous work has shown that the response is not mediated by PTH, other studies suggest that hypophosphatemia per se does not mediate the response. This raises the possibility that another hormone mediates that response. Previous work in this laboratory has shown that response is not qualitatively affected by the age or sex of the animals and is not dependent upon the presence of gonadal hormones. However, hypophysectomy completely abolishes the rise in plasma 1,25-(OH)2-D levels in response to dietary PO4 deprivation. These results support the hypothesis that a pituitary hormone acting either directly or indirectly on the kidney mediates the response. Experiments are in progress with hypophysectomized animals replaced with various hormones alone or in combination to determine the role of the pituitary in the mediation of the response.